Melanoma genetics and treatment
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Transcript of Melanoma genetics and treatment
A journey to the world of melanoma genetic and treatment
Lorenzo Alonso. Medical Oncology
A journey to the world of melanoma genetic and treatment
Lorenzo Alonso. Medical Oncology
The Facts
• Phase III vemurafenib vs DTIC: median OS 13,2 months vs 9,6 months(significant)
• 12 months OS: vemurafenib 55% vs 43% for dacarbazine.
• Duration of response limited due to development of resistance
• Ipilimumab: objective response uncommon(10-20%). Median OS vs gp100 10 vs 6,4 months. In a second study vs DTIC 3 year estimated survival rates 21% vs 12% (HR 0,72).
Braf inhibitor resistanceBraf inhibitor resistance
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Mutations “relevants”
BRAF (40-70%) melanomas
NRAS: 20% melanomas
PTEN: 20-40% melanomas
C-Kit: acral(36%), mucosas(39%) and CSD *((28%).
GNAQ y GNA11: > 50% uveal melanomas.
*CSD: Chronic sun damaged
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C-Kit
Mucosal, acral ( 2% each melanomas) and chronic sun damaged areas.
Mutación mope important than amplificatión
Drugs: Gleevec, Nilotinib, Dasatinib
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12
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“Killing” the “mad” BRAF loco
Vemurafenib
Dabrafenib
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Responses: Dabrafenib 50%
DTIC 6%
Median Progression-free survival:
5,1 vs 2,7 months for Dabrafenib
Responses: Dabrafenib 50%
DTIC 6%
Median Progression-free survival:
5,1 vs 2,7 months for Dabrafenib
Squamous cell carcinoma
Vemurafenib 26%
Dabrafenib 6%
Squamous cell carcinoma
Vemurafenib 26%
Dabrafenib 6%
BREAK-3BREAK-3
N-RAS mutation
(MEK 162)
GNAQ
Lancet Oncology 2013; 14: 249Lancet Oncology 2013; 14: 249
End-point response:
30patients 20%PR in NRAS mutated
Previous treatment allowed: no MEK inh or Ipilimumab
The most common grade 3-4 adverse event: an asymptomatic rise in CPK
“Retinal events” also commons
End-point response:
30patients 20%PR in NRAS mutated
Previous treatment allowed: no MEK inh or Ipilimumab
The most common grade 3-4 adverse event: an asymptomatic rise in CPK
“Retinal events” also commons
MEK inhibitors
.AZD6244: inhibe MEK1 y MEK2.GSK1120212(trametinib)
METRIC: Trametinib vs chemotherapy (Braf mutated)
Flaherty,K.
NEJM 2012; 367:107
Flaherty,K.
NEJM 2012; 367:107
Chemotherapy:DTIC or Taxol
47% chemotherapy arm crossed over to trametinib
At least one previous regimen
No Braf inh or Ipilimumab allowed
Chemotherapy:DTIC or Taxol
47% chemotherapy arm crossed over to trametinib
At least one previous regimen
No Braf inh or Ipilimumab allowed
Response rate: 22% vs 8%Response rate: 22% vs 8%
Dabrafenib (antiBRAF) alone or combined with trametinib(MEK inh)
Flaherty,K, NEJM 2012;367: 1694
The practical path
Melanoma diagnosisMelanoma diagnosis
ECOG 0-1ECOG 0-1
Braf mutBraf mut
“slow”“slow”
Clinical
agressive
Clinical
agressive
vemuravemura
Ipili o
vemura
Ipili o
vemura
Braf no mutBraf no mut
ipiliipili
Braf: Vemurafenib.Dabrafenib
MEK: trametinib. MEK 162
cKit: Imanitinib. Dasatinib.
NRAS: MEK162
GNAQ: MEK inh
Uveal: GNAQ 55%
GNA11 35%
CSD: chronic sun damaged
Melanoma genetic variants and therapeutic
Anatomical site
Marker Drugs Trials
Skin: non-chronic sun damaged
Braf (60%)
NRAS(10%)
Vemurafenib
DabrafenibMEK inh: trametinib
MEK162
Phase III
Phase II
Skin: sun damaged
Kit (25%)
Braf (5%)Imatinib
Dasatinib
Mucoses Kit (39%)NRAS (5%)
Phase II
Acral Kit (36%)
Braf (15%)
NRAS (10%)
Uveal GNAQ MEK inh:trametinib
trigafenibtrigafenib
albamumabalbamumab